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Imatinib inhibits colorectal cancer cell growth and suppresses stromal‐induced growth stimulation, MT1‐MMP expression and pro‐MMP2 activation
Author(s) -
Stahtea Xanthi N.,
Roussidis Andeas E.,
Kanakis Ioannis,
Tzanakakis George N.,
Chalkiadakis George,
Mavroudis Dimitris,
Kletsas Dimitris,
Karamanos Nikos K.
Publication year - 2007
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.23029
Subject(s) - imatinib , stromal cell , cancer research , cell growth , imatinib mesylate , cell culture , mmp2 , cancer cell , matrix metalloproteinase , tyrosine kinase inhibitor , chemistry , biology , cancer , medicine , metastasis , biochemistry , genetics , myeloid leukemia
Tumor progress depends on the proliferation of cancer cells, their interactions with stroma and the proteolytic action of enzymes. Colon cancer is c‐kit positive and responsive to the specific tyrosine kinase inhibitor imatinib. We investigated the effect of imatinib on the proliferation of a panel of epithelial colon cancer cell lines in presence and absence of the antimetabolite 5‐FU, and the effect of conditioned media (CM) derived from colon stromal fibroblasts with and without previous exposure to imatinib. The effects of imatinib on gene expression of MMPs and TIMPs were also studied. Imatinib effectively inhibited the proliferation of all cell lines, showing IC 50 from 0.3 to 3 μM. Its combination with 5‐FU significantly enhances the growth inhibition of the highly tumourigenic HT‐29 cells. CM derived from stromal fibroblasts induced the proliferation of the HT‐29 cells; this stimulatory effect was abolished upon treatment with CM obtained after exposure of fibroblasts to imatinib. Gene expression of MT1‐, MT2‐MMP and MMP‐7 was also inhibited depending on the cell line, whereas that of TIMP‐2 was not affected. CM stimulated MT1‐MMP protein expression by HT‐29; this stimulatory effect was suppressed in the presence of imatinib. Activation of pro‐MMP2 to MMP2 in culture medium of HT‐29 treated with CM was increased and this activity was inhibited in presence of imatinib. The obtained data showed that imatinib is a powerful inhibitor of human colon cancer cell growth and effectively suppresses the stromal‐induced stimulation of cancer cell growth and activation of proMMP2. Further studies are warranted to evaluate the in vivo effects. © 2007 Wiley‐Liss, Inc.